Radiopharmacokinetic Modelling and Radiation Dose Assessment of 223ra Used for Treatment of Metastatic Castration Resistant Prostate Cancer

Abstract Purpose Ra-223-Dichloride (223Ra, Xofigo®) is used for treatment of patients suffering from castration-resistant metastatic prostate cancer. The objective of this work was to apply the most recent biokinetic model for radium and its progeny and dosimetric framework developed by the International Commission on Radiological Protection (ICRP) and to show their radiopharmacokinetic behaviour. Organ absorbed and equivalent doses after intravenous injection of 223Ra were estimated and compared to clinical data and other modelling study. Methods The most recent ICRP systemic biokinetic model of 223Ra and its progeny as well as the ICRP human alimentary tract model were applied for the radiopharmacokinetic modelling of Xofigo® biodistribution in patients after bolus administration. Independent kinetics was assumed for the progeny of 223Ra. The time activity curves for 223Ra were modelled and the time integrated activity coefficients, in the source regions for each progeny were determined. For estimating the organ absorbed doses, the Specific Absorbed Fractions (SAF) and dosimetric framework of ICRP were used together with the aforementioned values to estimate the organ absorbed and equivalent doses. Results The distribution of 223Ra after injection showed a rapid plasma clearance and a low urinary excretion. Main elimination was via faeces. Bone retention was found to be about 30% at 4 h post-injection. Similar tendencies were observed in clinic trials. The highest absorbed dose coefficients were found for bone endosteum, liver, and red marrow, followed by kidneys and colon. Conclusion The biokinetic modelling of 223Ra and its progeny may help to predict their distributions in patients after administration of Xofigo®. The organ dose coefficients of this work showed some variation to the values from clinical studies and of a previous compartmental modelling study. The dose to the bone endosteum was found to be lower by a factor of ca. 3 than previously estimated.

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Radiopharmacokinetic modelling and radiation dose assessment of 223Ra used for treatment of metastatic castration-resistant prostate cancer

EJNMMI Physics ◽

10.1186/s40658-021-00388-1 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Vera Höllriegl ◽

Nina Petoussi-Henss ◽

Kerstin Hürkamp ◽

Juan Camilo Ocampo Ramos ◽

Wei Bo Li

Keyword(s):

Prostate Cancer ◽

Radiological Protection ◽

Bolus Administration ◽

Time Activity ◽

Biokinetic Model ◽

Castration Resistant ◽

Absorbed Doses ◽

Red Marrow ◽

Dose Coefficients ◽

Modelling Study

Abstract Purpose Ra-223 dichloride (223Ra, Xofigo®) is used for treatment of patients suffering from castration-resistant metastatic prostate cancer. The objective of this work was to apply the most recent biokinetic model for radium and its progeny to show their radiopharmacokinetic behaviour. Organ absorbed doses after intravenous injection of 223Ra were estimated and compared to clinical data and data of an earlier modelling study. Methods The most recent systemic biokinetic model of 223Ra and its progeny, developed by the International Commission on Radiological Protection (ICRP), as well as the ICRP human alimentary tract model were applied for the radiopharmacokinetic modelling of Xofigo® biodistribution in patients after bolus administration. Independent kinetics were assumed for the progeny of 223Ra. The time activity curves for 223Ra were modelled and the time integrated activity coefficients, $$ \overset{\sim }{a}\left({r}_S,{T}_D\right), $$ a ~ r S T D , in the source regions for each progeny were determined. For estimating the organ absorbed doses, the Specific Absorbed Fractions (SAF) and dosimetric framework of ICRP were used together with the aforementioned $$ \overset{\sim }{a}\left({r}_S,{T}_D\right) $$ a ~ r S T D values. Results The distribution of 223Ra after injection showed a rapid plasma clearance and a low urinary excretion. Main elimination was via faeces. Bone retention was found to be about 30% at 4 h post-injection. Similar tendencies were observed in clinical trials of other authors. The highest absorbed dose coefficients were found for bone endosteum, liver and red marrow, followed by kidneys and colon. Conclusion The biokinetic modelling of 223Ra and its progeny may help to predict their distributions in patients after administration of Xofigo®. The organ dose coefficients of this work showed some variation to the values reported from clinical studies and an earlier compartmental modelling study. The dose to the bone endosteum was found to be lower by a factor of ca. 3 than previously estimated.

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Biodistribution and dosimetry of a single dose of albumin-binding ligand [177Lu]Lu-PSMA-ALB-56 in patients with mCRPC

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-020-05022-3 ◽

2020 ◽

Author(s):

Vasko Kramer ◽

René Fernández ◽

Wencke Lehnert ◽

Luis David Jiménez-Franco ◽

Cristian Soza-Ried ◽

...

Keyword(s):

Prostate Cancer ◽

Whole Body ◽

Published Data ◽

Albumin Binding ◽

Castration Resistant Prostate Cancer ◽

Effective Treatment Option ◽

Binding Properties ◽

Castration Resistant ◽

Red Marrow ◽

Therapeutic Outcomes

Abstract Introduction PSMA-targeted radionuclide therapy with lutetium-177 has emerged as an effective treatment option for metastatic, castration-resistant prostate cancer (mCRPC). Recently, the concept of modifying PSMA radioligands with an albumin-binding entity was demonstrated as a promising measure to increase the tumor uptake in preclinical experiments. The aim of this study was to translate the concept to a clinical setting and evaluate the safety and dosimetry of [177Lu]Lu-PSMA-ALB-56, a novel PSMA radioligand with albumin-binding properties. Methods Ten patients (71.8 ± 8.2 years) with mCRPC received an activity of 3360 ± 393 MBq (120–160 μg) [177Lu]Lu-PSMA-ALB-56 followed by whole-body SPECT/CT imaging over 7 days. Volumes of interest were defined on the SPECT/CT images for dosimetric evaluation for healthy tissue and tumor lesions. General safety and therapeutic efficacy were assessed by measuring blood biomarkers. Results [177Lu]Lu-PSMA-ALB-56 was well tolerated, and no severe adverse events were observed. SPECT images revealed longer circulation of [177Lu]Lu-PSMA-ALB-56 in the blood with the highest uptake in tumor lesions at 48 h post injection. Compared with published data for other therapeutic PSMA radioligands (e.g. PSMA-617 and PSMA I&T), normalized absorbed doses of [177Lu]Lu-PSMA-ALB-56 were up to 2.3-fold higher in tumor lesions (6.64 ± 6.92 Gy/GBq) and similar in salivary glands (0.87 ± 0.43 Gy/GBq). Doses to the kidneys and red marrow (2.54 ± 0.94 Gy/GBq and 0.29 ± 0.07 Gy/GBq, respectively) were increased. Conclusion Our data demonstrated that the concept of albumin-binding PSMA-radioligands is feasible and leads to increased tumor doses. After further optimization of the ligand design, the therapeutic outcomes may be improved for patients with prostate cancer.

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Uncertainty quantification of bioassay functions for the internal dosimetry of radioiodine

Journal of Radiation Research ◽

10.1093/jrr/rraa081 ◽

2020 ◽

Vol 61 (6) ◽

pp. 860-870

Author(s):

Tae-Eun Kwon ◽

Yoonsun Chung ◽

Jaeryong Yoo ◽

Wi-Ho Ha ◽

Minsu Cho

Keyword(s):

Measurement Data ◽

Dose Assessment ◽

Internal Dosimetry ◽

High Dose ◽

Radiological Protection ◽

Retention Function ◽

Internal Dose ◽

Actual Measurement ◽

Monte Carlo Simulation Technique ◽

Biokinetic Model

Abstract Bioassay functions, which are provided by the International Commission on Radiological Protection, are used to estimate the intake activity of radionuclides; however, they include considerable uncertainties in terms of the internal dosimetry for a particular individual. During a practical internal dose assessment, the uncertainty in the bioassay function is generally not introduced because of the difficulty in quantification. Therefore, to clarify the existence of uncertainty in the bioassay function and provide dosimetrists with an insight into this uncertainty, this study attempted to quantify the uncertainty in the thyroid retention function used for radioiodine exposure. The uncertainty was quantified using a probabilistic estimation of the thyroid retention function through the propagation of the distribution of biokinetic parameters by the Monte Carlo simulation technique. The uncertainties in the thyroid retention function, expressed in terms of the scattering factor, were in the ranges of 1.55–1.60 and 1.40–1.50 for within 24 h and after 24 h, respectively. In addition, the thyroid retention function within 24 h was compared with actual measurement data to confirm the uncertainty due to the use of first-order kinetics in the biokinetic model calculation. Significantly higher thyroid uptakes (by a factor of 1.9) were observed in the actual measurements. This study indicates that consideration of the uncertainty in the thyroid retention function can avoid a significant over- and under-estimation of the internal dose, particularly when a high dose is predicted.

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177Lu-DOTA-HYNIC-Lys(Nal)-Urea-Glu: Biokinetics, Dosimetry, and Evaluation in Patients with Advanced Prostate Cancer

Contrast Media & Molecular Imaging ◽

10.1155/2018/5247153 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 4

Author(s):

Clara Santos-Cuevas ◽

Guillermina Ferro-Flores ◽

Francisco O. García-Pérez ◽

Nallely Jiménez-Mancilla ◽

Gerardo Ramírez-Nava ◽

...

Keyword(s):

Prostate Cancer ◽

Healthy Subjects ◽

Slow Component ◽

Optimal Number ◽

Molecular Probe ◽

Whole Body ◽

Body Images ◽

Time Activity ◽

Biokinetic Model ◽

Before And After

SPECT/CT images in patients have demonstrated the ability of [99mTc]Tc-EDDA/HYNIC-Lys(Nal)-Urea-Glu ([99mTc]Tc-iPSMA) to detect tumors and metastases of prostate cancer. Considering that theranostics combines the potential of therapeutic and diagnostic radionuclides in the same molecular probe, the aim of this research was to estimate the biokinetics and dosimetry of 177Lu-DOTA-HYNIC-Lys(Nal)-Urea-Glu (177Lu-iPSMA) in healthy subjects and analyze the response in patients receiving 177Lu-iPSMA therapeutic doses. 177Lu-iPSMA was obtained from lyophilized formulations with radiochemical purities >98%. Whole-body images from five healthy subjects were acquired at 20 min, 6, 24, 48, and 120 h after 177Lu-iPSMA administration (185 MBq). The image sequence was used to extrapolate the 177Lu-iPSMA time-activity curves of each organ to adjust the biokinetic model and calculate the total number of disintegrations (N) that occurred in the source regions. N data were the input for the OLINDA/EXM code to calculate internal radiation doses. Ten patients (median age: 68 y; range 58–86 y) received from 1 to 4 cycles of 177Lu-iPSMA (3.7 or 7.4 GBq) every 8–10 weeks. Response was evaluated using the 68Ga-PSMA-ligand-PET/CT or 99mTc-iPSMA-SPECT/CT diagnostic images and serum PSA levels before and after 177Lu-iPSMA treatment. The blood activity showed a half-life value of 1.1 h for the fast component (T1/2α = ln2/0.614), 9.2 h for the first slow component (T1/2β = ln2/0.075), and 79.6 h for the second slow component (T1/2γ = ln2/0.008). The average absorbed doses were 0.23, 0.28, 0.88, and 1.17 Gy/GBq for the spleen, liver, kidney, and salivary glands. A total of 18 cycles were performed in 10 patients. A PSA decrease and some reduction of the radiotracer uptake (SUV) in tumor lesions occurred in 60% and 70% of the patients, respectively. 177Lu-iPSMA obtained from kit formulations showed high tumor uptake with good response rates in patients. The results obtained in this study warrant further clinical studies to establish the optimal number of treatment cycles and for evaluating the effect of this therapeutic agent on survival of patients.

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ICRP Task Group 95: internal dose coefficients

Annals of the ICRP ◽

10.1177/0146645318759620 ◽

2018 ◽

Vol 47 (3-4) ◽

pp. 63-74 ◽

Cited By ~ 2

Author(s):

F. Paquet ◽

J. Harrison

Keyword(s):

Dose Assessment ◽

Radiological Protection ◽

Monitoring Methods ◽

The Public ◽

The Past ◽

Workplace Monitoring ◽

Dose Coefficients ◽

Bioassay Data ◽

General Aspects ◽

Icrp Publication

Internal doses are calculated using biokinetic and dosimetric models. These models describe the behaviour of the radionuclides after ingestion, inhalation, and absorption to the blood, and the absorption of the energy resulting from their nuclear transformations. The International Commission on Radiological Protection (ICRP) develops such models and applies them to provide dose coefficients and bioassay functions for the calculation of equivalent or effective dose from knowledge of intakes and/or measurements of activity in bioassay samples. Over the past few years, ICRP has devoted a considerable amount of effort to the revision and improvement of models to make them more physiologically realistic representations of uptake and retention in organs and tissues, and of excretion. Provision of new biokinetic models, dose coefficients, monitoring methods, and bioassay data is the responsibility of Committee 2 and its task groups. Three publications in a series of documents replacing the ICRP Publication 30 series and ICRP Publications 54, 68, and 78 have been issued [Occupational Intakes of Radionuclides (OIR) Parts 1–3]. OIR Part 1 describes the assessment of internal occupational exposure to radionuclides, biokinetic and dosimetric models, methods of individual and workplace monitoring, and general aspects of retrospective dose assessment. OIR Parts 2–5 provide data on individual elements and their radioisotopes. Work is also in progress on revision of dose coefficients for radionuclide intakes by members of the public.

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PRACTICAL METHODS FOR INTERNAL DOSE ASSESSMENT FOR RADIOIODINE INTAKE AFTER THYROID BLOCKING: CLASSIFICATION OF DEGREE OF BLOCKAGE AND DETERMINATION OF INSENSITIVE MEASUREMENT POINT

Radiation Protection Dosimetry ◽

10.1093/rpd/ncz139 ◽

2019 ◽

Vol 187 (1) ◽

pp. 69-76 ◽

Cited By ~ 1

Author(s):

Tae-Eun Kwon ◽

MinSeok Park ◽

Gyu-Hwan Jung ◽

Yoonsun Chung ◽

Wi-Ho Ha ◽

...

Keyword(s):

Dose Assessment ◽

Internal Dose ◽

Urine Excretion ◽

Normal Thyroid ◽

Considerable Uncertainty ◽

Biokinetic Model ◽

Dosimetric Data ◽

Dose Coefficients

Abstract Iodine thyroid blocking (ITB) suppresses the uptake of iodine to the thyroid and reduces internal doses after radioiodine intake; however, its disturbance of thyroid biokinetics causes considerable uncertainty in the use of dosimetric data intended for assessment of unblocked normal thyroid. To more accurately assess internal dose after ITB, practical dosimetry methods were proposed that consider the ITB effect in a dosimetric manner. A method using the ratio of urine excretion to thyroid retention activity was proposed to retrospectively determine individual-specific ITB levels; bioassay functions and dose coefficients corresponding to ITB levels were calculated separately using the latest biokinetic model and fundamental data. Moreover, insensitive measurement points of time, which led to similar results regardless of ITB level, were determined based on the dose per unit content. Proposed insensitive points for inhalation of vapour forms and particulate forms, respectively, were 1.5 days and 2 days after exposure.

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EURADOS work on internal dosimetry

Annals of the ICRP ◽

10.1177/0146645318756232 ◽

2018 ◽

Vol 47 (3-4) ◽

pp. 75-82 ◽

Cited By ~ 3

Author(s):

B. Breustedt ◽

E. Blanchardon ◽

C-M. Castellani ◽

G. Etherington ◽

D. Franck ◽

...

Keyword(s):

Dose Assessment ◽

Assessment Process ◽

Internal Dosimetry ◽

Biokinetic Model ◽

Intercomparison Exercises ◽

Training Courses ◽

Dose Coefficients ◽

Sensitive Parameters ◽

Structured Approach ◽

Technical Recommendations

European Radiation Dosimetry Group (EURADOS) Working Group 7 is a network on internal dosimetry that brings together researchers from more than 60 institutions in 21 countries. The work of the group is organised into task groups that focus on different aspects, such as development and implementation of biokinetic models (e.g. for diethylenetriamine penta-acetic acid decorporation therapy), individual monitoring and the dose assessment process, Monte Carlo simulations for internal dosimetry, uncertainties in internal dosimetry, and internal microdosimetry. Several intercomparison exercises and training courses have been organised. The IDEAS guidelines, which describe – based on the International Commission on Radiological Protection’s (ICRP) biokinetic models and dose coefficients – a structured approach to the assessment of internal doses from monitoring data, are maintained and updated by the group. In addition, Technical Recommendations for Monitoring Individuals for Occupational Intakes of Radionuclides have been elaborated on behalf of the European Commission, DG-ENER (TECHREC Project, 2014–2016, coordinated by EURADOS). Quality assurance of the ICRP biokinetic models by calculation of retention and excretion functions for different scenarios has been performed and feedback was provided to ICRP. An uncertainty study of the recent caesium biokinetic model quantified the overall uncertainties, and identified the sensitive parameters of the model. A report with guidance on the application of ICRP biokinetic models and dose coefficients is being drafted at present. These and other examples of the group’s activities, which complement the work of ICRP, are presented.

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